The frequent detection in sera of humans infected with the human immunodeficiency virus (HIV-1) of antibodies enhancing the infectivity of HIV-1 (EAb) has been reported. The level of EAb in such sera usually exceeded the level of virus-neutralizing antibodies (VNAb). On the other hand, some anti-HIV-1 positive sera contained VNAb but no detectable EAb, suggesting that VNAb and EAb recognize distinct epitopes on the envelope glycoproteins (gp120 and gp41) of HIV-1. EAb generated during HIV-1 infection. EAb elicited by immunization with gp120/gp41 may diminish or abrogate the protective efficacy of other antibodies involved in HIV-=1 neutralization and in elimination of HIV-1 and of HIV-1 infected cells. The design of HIV-1 protective immunogens will be facilitated by: (1) identification of epitopes recognized by EAb and (2) understanding the mechanism of virus enhancement. We propose to define gp120/gp41 epitopes involved in enhancement of HIV- 1 infectivity for monocytes using: (a) anti-peptide antisera and (b) specific antibodies isolated from human anti HIV-positive sera by affinity chromatography on distinct synthetic peptides linked to a solid support. Reagents for the proposed research are available (5) peptides (19-26 amino acid residues long) from nearly the entire length of gp120 and gp41 and the corresponding antisera]. After establishing the specificity of EAb, the site of entry of the infectious HIV-1-antibody (Ab) complexes into cells will be defined by following the inhibitory effect of antibodies to: (a) the CD4 (T4) receptor for HIV-1; (b) Fc receptors; and (c) complement C3b receptors on alpha) the infectivity of HIV-1 Ab complexes and Beta) the uptake of gp120/gp41 in the absence and presence of EAb with defined epitope specificity.